Abstract

The role of transcription factors (TFs) in modulating post-ischemic cerebral inflammation is not evaluated in detail. While Egr1 (NGFI-A/Krox24) is a TF that promotes inflammatory gene expression, at least 2 other TFs can control Egr1. Of these, c-EBP-beta can stimulate and PPAR-gamma can inhibit Egr1 induction. We hypothesize that after focal ischemia (1) EgM induction contributes to inflammation and brain damage; (2) c-EBP-beta is an upstream TF that induces Egr1 expression and inflammation; and (3) PPAR-gamma activation can curtail Egr1 induction and inflammation. Preliminary studies showed (a) sustained upregulation of Egr1, c-EBP-beta and PPAR-gamma expression after focal ischemia; (b) smaller infarcts in Egr1 null mice and bigger infarcts in EgM adenoviral transfected rats after focal ischemia, (c) curtailed post-ischemic inflammatory gene expression in EgM null mice, (d) less brain damage, decreased inflammation and less Egr1 induction in c-EBP-beta knockout mice after focal ischemia, and (e) prevention of post-ischemic EgM induction, inflammation and infarction by treatment with PPAR-gamma agonists. Using antisense knockdown, adenovirus-induced overexpression, and null mice, we will evaluate the functional significance and the interactive mechanism of action of these transcription factors in modulating inflammation and neuronal damage after transient focal ischemia in rodent brain. We will study if (a) Egr-1 knockdown prevents and Egr-1 overexpression exacerbates post-ischemic inflammation and brain damage; (b) Ischemia in Egr-1 knockout mice results in less inflammation and smaller infarcts; (c) C-EBP beta knockout mice show curtailed EgM induction, decreased inflammation and less neuronal damage after ischemia; and (d) PPAR-gamma agonists decrease the post-ischemic inflammation and brain damage by preventing EgM induction. The ultimate goal is to define the role of EgM and its regulators to develop therapies to control cerebral inflammation at the level of transcription.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS049448-03
Application #
7345388
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Jacobs, Tom P
Project Start
2006-01-01
Project End
2009-12-31
Budget Start
2008-01-01
Budget End
2008-12-31
Support Year
3
Fiscal Year
2008
Total Cost
$251,549
Indirect Cost

  Institution

Name
University of Wisconsin Madison
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715

  Publications

Tureyen, Kudret; Bowen, Kellie; Liang, Jin et al. (2011) Exacerbated brain damage, edema and inflammation in type-2 diabetic mice subjected to focal ischemia. J Neurochem 116:499-507
Dharap, Ashutosh; Vemuganti, Raghu (2010) Ischemic pre-conditioning alters cerebral microRNAs that are upstream to neuroprotective signaling pathways. J Neurochem 113:1685-91
Dharap, Ashuthosh; Bowen, Kellie; Place, Robert et al. (2009) Transient focal ischemia induces extensive temporal changes in rat cerebral microRNAome. J Cereb Blood Flow Metab 29:675-87
Lang, Bradley T; Yan, Yiping; Dempsey, Robert J et al. (2009) Impaired neurogenesis in adult type-2 diabetic rats. Brain Res 1258:25-33
Kapadia, Ramya; Yi, Jae-Hyuk; Vemuganti, Raghu (2008) Mechanisms of anti-inflammatory and neuroprotective actions of PPAR-gamma agonists. Front Biosci 13:1813-26
Yi, Jae-Hyuk; Park, Seung-Won; Brooks, Nathaniel et al. (2008) PPARgamma agonist rosiglitazone is neuroprotective after traumatic brain injury via anti-inflammatory and anti-oxidative mechanisms. Brain Res 1244:164-72
Tureyen, Kudret; Brooks, Nathaniel; Bowen, Kellie et al. (2008) Transcription factor early growth response-1 induction mediates inflammatory gene expression and brain damage following transient focal ischemia. J Neurochem 105:1313-24
Yi, Jae-Hyuk; Park, Seung-Won; Kapadia, Ramya et al. (2007) Role of transcription factors in mediating post-ischemic cerebral inflammation and brain damage. Neurochem Int 50:1014-27
Park, Seung-Won; Yan, Yi-Ping; Satriotomo, Irawan et al. (2007) Substance P is a promoter of adult neural progenitor cell proliferation under normal and ischemic conditions. J Neurosurg 107:593-9
Yan, Yi-Ping; Sailor, Kurt A; Lang, Bradley T et al. (2007) Monocyte chemoattractant protein-1 plays a critical role in neuroblast migration after focal cerebral ischemia. J Cereb Blood Flow Metab 27:1213-24

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